RNA editing (ADAR) therapeutics

01Overview and value chain

Markers: [EC: FDA orphan-drug designation + accelerated-approval pathway; Directive 2001/83/EC | OECD: Bio-pharma | Regulator: FDA (USA), EMA (European Union), NMPA (China)]

RNA editing therapeutics correct disease-causing transcripts at the RNA level rather than in the genome. Engineered oligonucleotides — Wave’s AIMers, Korro’s OPERA guides, ProQR’s Axiomer EONs, HuidaGene’s arRNAs — recruit the cell’s endogenous adenosine deaminase acting on RNA (ADAR) enzymes to convert a pathogenic adenosine to inosine (A-to-I, read as guanosine), repairing mutant mRNA without any permanent change to the DNA. Because the edit is made on the transcript, it is reversible and dose-titratable, with no bystander edits, no indels and no lasting genome alteration — the safety advantages the modality holds over DNA base editing. The field’s lead asset, Wave’s WVE-006 (a GalNAc-conjugated AIMer for alpha-1 antitrypsin deficiency, AATD), generated wild-type M-AAT at 64% of total AAT and cut toxic Z-AAT by 71% in the RestorAATion-2 trial, reaching 11.9 µM total AAT with editing sustained for at least three months after the last dose; ProQR’s AX-0810 then delivered the first clinical validation of an RNA-editing platform with an 8-fold NTCP target-engagement signal, and Korro’s KRRO-111 achieved more than 90% SERPINA1 editing in vivo. Delivery is dominated by subcutaneous GalNAc conjugation that routes the oligo to hepatocytes via ASGPR, avoiding lipid nanoparticles; no RNA-editing drug is approved yet, and FDA feedback on an accelerated-approval pathway for WVE-006 is expected mid-2026.

The key directions of RNA editing therapeutics are:

1. AATD RNA editors (AATD Editor): GalNAc ADAR-recruiting oligonucleotides that repair the SERPINA1 Z-allele transcript, restoring protective M-AAT and clearing toxic Z-AAT in the liver — Wave (WVE-006), Korro (KRRO-110, KRRO-111).
2. Liver and metabolic editors (Metabolic Editor): RNA editing of hepatocyte transporters and metabolic enzymes beyond AATD — ProQR (AX-0810/AX-0811 on NTCP for cholestatic liver disease, AX-2911 on PNPLA3 for MASH).
3. ADAR-recruitment platforms (Editing Platform): the guide-RNA and chemically modified oligonucleotide chemistries that recruit endogenous ADAR1/ADAR2 without delivering any exogenous enzyme — Wave AIMer, Korro OPERA, ProQR Axiomer, HuidaGene LEAPER.
4. CNS and rare-disease editors (CNS Editor): extension of A-to-I editing to neuronal and rare-genetic targets through partnered programs — ProQR (AX-2402 for Rett syndrome MECP2, with the Rett Syndrome Research Trust; Eli Lilly CNS collaboration).

Sectoral value chain

[pathogenic A-to-I target on mRNA] ──> [ADAR-recruiting oligo (AIMer/EON/arRNA) design + synthesis] ──> [GalNAc-conjugated subcutaneous editor]
                                                       │
                                              (endogenous ADAR A-to-I edit, reversible)
                                                       │
                                                       ▼
[clinical candidate] <─── [editing PD/PK + Phase 1-2 trials] <─────┘

Value chain levels

Cross-cutting technologies of the sector:

• Endogenous ADAR recruitment (ADAR Recruitment): all four platforms recruit the cell’s own ADAR1/ADAR2 via a guide oligo, avoiding exogenous-protein delivery and so lowering cargo size and immunogenicity versus CRISPR-base-editor proteins.
• GalNAc hepatocyte delivery (GalNAc Delivery): subcutaneous GalNAc conjugation routes the editor to hepatocytes through the asialoglycoprotein receptor, enabling liver-directed A-to-I editing without lipid nanoparticles and supporting infrequent (monthly or longer) dosing.
• Reversible, titratable editing (Reversible Editing): because the edit sits on the transcript and not the genome, RNA editing is transient and dose-adjustable, with no bystander edits or permanent genome change — the central safety differentiator versus DNA editing.

02US

The US leads RNA-editing therapeutics clinically, with the field’s two most advanced AATD programs — Wave’s WVE-006 in Phase 1b/2a and Korro’s OPERA platform — both run from Cambridge, MA, under an FDA framework built on orphan-drug designation and the accelerated-approval pathway.

Wave, Korro, FDA

• Wave Life Sciences: WVE-006, a GalNAc-conjugated AIMer for AATD, is the modality’s lead asset; RestorAATion-2 data (May 2026) showed 64% wild-type M-AAT, a 71% reduction in toxic Z-AAT, 11.9 µM total AAT on 200 mg biweekly dosing (13.6 µM on 400 mg monthly), and editing sustained at least three months after the last dose, with no liver toxicities; FDA feedback on an accelerated-approval pathway is expected mid-2026.
• Korro Bio: the OPERA (Oligonucleotide Promoted Editing of RNA) platform underpins KRRO-110 (in the REWRITE Phase 1/2a study, with FDA orphan-drug designation granted in March 2025) and the newly selected development candidate KRRO-111, which achieved more than 90% SERPINA1 transcript editing and roughly 90% repaired functional AAT protein in a PiZZ mouse model; the company held $157.1M in cash and marketable securities at 31 March 2026, with a runway into H2 2028.
• FDA framework: RNA-editing oligonucleotides are reviewed under the FDA’s oligonucleotide-therapeutics pathway, with orphan-drug designation and the accelerated-approval route available for AATD (a rare disease affecting fewer than 200,000 people in the US); WVE-006’s mid-2026 regulatory feedback is the modality’s first such checkpoint.

03CN

China’s RNA-editing strength is foundational rather than commercial: Wensheng Wei’s group at Peking University and Changping Laboratory originated the LEAPER platform, whose 2026 LEAPER 3.0 iteration is the field’s leading structure-guided guide-RNA design, with HuidaGene as the translation vehicle.

HuidaGene, LEAPER, NMPA

• HuidaGene: is commercializing the LEAPER (Leveraging Endogenous ADAR for Programmable Editing of RNA) platform from Wei’s PKU lab; LEAPER uses a single engineered ADAR-recruiting RNA (arRNA) to direct endogenous ADAR to a target adenosine, with no exogenous enzyme and therefore low immunogenicity and a small delivery payload.
• LEAPER lineage: LEAPER 1.0 was published in Nature Biotechnology in 2019 (linear arRNA), LEAPER 2.0 in 2022 introduced circular circ-arRNA for higher editing efficiency and lower off-target editing, and LEAPER 3.0 (Cell, 10 June 2026) uses AlphaFold 3 structural prediction to design dual-bulge arRNAs that expand the set of editable sites and eliminate bystander editing.
• NMPA framework: RNA-editing therapeutics are reviewed under the NMPA’s oligonucleotide and biologics framework; the LEAPER platform’s progress rests on National Natural Science Foundation of China funding (grants 82341207 and 31930016) and Beijing municipal science-and-technology support, with clinical translation still ahead of the US leaders.

04EU

Europe’s role in RNA editing is concentrated in ProQR Therapeutics (Leiden, NL), whose Axiomer platform delivered the first clinical validation of an RNA-editing oligonucleotide and is scaled through a deepening Eli Lilly partnership.

ProQR, Axiomer, EMA

• ProQR Therapeutics: the Axiomer platform uses ADAR-recruiting editing oligonucleotides (EONs); AX-0810, a GalNAc-conjugated EON modulating NTCP for cholestatic liver disease, produced the first clinical validation of the platform in 2026 — a dose-dependent up to 8-fold rise in total bile acids at 6 mg/kg (above the 2-fold target-engagement threshold) with an estimated half-life of about 8 weeks and no serious adverse events; the follow-on AX-0811 has a clinical-trial application planned mid-2026, and development candidates AX-2402 (Rett syndrome) and AX-2911 (MASH) extend the pipeline.
• Eli Lilly partnership: Lilly has been tied to the Axiomer platform since 2021 (liver and nervous-system targets), expanded in 2022, with ProQR eligible for up to about $3.75bn in milestones plus royalties; Lilly maintained its pro-rata ownership in ProQR’s $59.2M June 2026 raise (buying about $9.2M of shares alongside a $50M public offering at $1.81 per share).
• EMA framework: RNA-editing oligonucleotides will be reviewed as MAA drugs by the European Medicines Agency under Directive 2001/83/EC; ProQR divested its late-stage ophthalmic assets (sepofarsen, ultevursen) in 2023 to focus entirely on Axiomer, and no RNA-editing drug is yet EU-approved.

05Leading companies and research institutes

06Tech stack and innovations

The stack pairs ADAR-recruiting oligonucleotide chemistry with GalNAc hepatocyte delivery and structure-guided guide-RNA design, yielding a reversible A-to-I edit on a disease transcript.

1. ADAR-recruiting oligonucleotides (Editing Oligo):
   • Wave’s AIMer (stereopure), Korro’s OPERA, ProQR’s Axiomer EON and HuidaGene’s arRNA are chemically modified oligos that recruit endogenous ADAR1/ADAR2 to a target adenosine; WVE-006 generated 64% M-AAT with a 71% Z-AAT reduction and editing sustained at least three months, while KRRO-111 reached more than 90% SERPINA1 transcript editing and roughly 90% repaired AAT protein in vivo.
2. GalNAc hepatocyte delivery (GalNAc Delivery):
   • subcutaneous GalNAc conjugation targets the asialoglycoprotein receptor on hepatocytes, enabling liver-directed editing without lipid nanoparticles; AX-0810 showed an 8-fold NTCP target-engagement signal at 6 mg/kg with an approximately 8-week half-life, and WVE-006 is dosed 200 mg biweekly or 400 mg monthly with a dynamic AAT response (up to 20.6 µM total AAT during an acute-phase response).
3. Structure-guided arRNA design (Guide Design):
   • rational engineering of the ADAR-recruiting guide to expand the editable sequence space and remove bystander edits; HuidaGene’s LEAPER 3.0 (Cell, 2026) uses AlphaFold 3 to model the ADAR1/ADAR2–double-stranded-RNA interface and introduces inner and outer bulge structures that confine catalysis to the target adenosine.

07Value chains and production pipelines

Industrial pipeline of an ADAR RNA-editing therapeutic (NDA / MAA, Directive 2001/83/EC)

┌───────────────────────────┐      ┌───────────────────────────┐
│ 1. Target & SNV selection │ ───> │ 2. arRNA/EON design       │
└───────────────────────────┘      └───────────────────────────┘
                                                  │
                                                  ▼
┌───────────────────────────┐      ┌───────────────────────────┐
│ 4. Preclinical & clinical │ <─── │ 3. GalNAc conjugation &   │
└───────────────────────────┘      │    CMC                    │
               │                    └───────────────────────────┘
               ▼
┌───────────────────────────┐      ┌───────────────────────────┐
│ 5. Regulatory & approval  │ ───> │ 6. Launch & PV            │
└───────────────────────────┘      └───────────────────────────┘

Stage 1: Target and SNV selection

A pathogenic G-to-A transcript variant correctable by A-to-I editing is identified (for example the SERPINA1 Z-allele in AATD or the NTCP transporter in cholestatic liver disease), together with an ADAR-recruitment-compatible sequence context around the target adenosine.

Stage 2: arRNA/EON design

An ADAR-recruiting oligonucleotide — an AIMer (Wave), OPERA guide (Korro), Axiomer EON (ProQR) or arRNA (HuidaGene) — is engineered with stereopure chemistry and, in LEAPER 3.0, dual-bulge structures that position endogenous ADAR on the target adenosine while suppressing bystander editing.

Stage 3: GalNAc conjugation and CMC

The editing oligo is conjugated to a GalNAc ligand for ASGPR-mediated hepatocyte uptake and manufactured under stereopure oligonucleotide GMP, yielding a subcutaneously delivered drug substance that avoids lipid-nanoparticle formulation.

Stage 4: Preclinical and clinical

Editing-efficiency, PK and safety studies support IND filing and first-in-human trials; WVE-006 is in the RestorAATion-2 Phase 1b/2a trial (11.9 µM total AAT, 71% Z-AAT reduction, editing held at least three months), KRRO-110 is in the REWRITE Phase 1/2a study, and AX-0810 produced the first clinical target-engagement validation of an RNA-editing platform (8-fold bile-acid response at 6 mg/kg).

Stage 5: Regulatory and approval

A NDA (US) or MAA (EU) is filed as an oligonucleotide therapeutic under Directive 2001/83/EC, with orphan-drug designation and the accelerated-approval pathway available for rare indications such as AATD; FDA feedback on an accelerated-approval route for WVE-006 is expected mid-2026.

Stage 6: Launch and pharmacovigilance

Following approval, the reversible-edit drug launches under the oligonucleotide pharmacovigilance regime, with real-world monitoring of editing durability and re-dosing interval that the modality has not yet seen at scale, no RNA-editing drug being yet approved.